Antiretroviral therapy (ART) has been effective in treating HIV infection for many people living with HIV (PLWH). ART enables most PLWH to live near-normal lifespans. We have shown that ~90% of PLWH in clinical care in 2016 had an undetectable viral load (VL). However, a number of factors influence the 10% who are not yet undetectable, many of whom face challenges from substance use. Even for those who suppress, threats of toxicities remain, and there are variable CD4 recovery and toxicity rates. The proposed research will identify genetic variants that contribute to outcomes including poorer responses and greater toxicities from ART among all PLWH and particularly for current and prior injection drug users (IDU). We will: Aim 1. Determine patterns and predictors of VL suppression and CD4 recovery by ART regimen overall and among key subgroups including current and prior IDU and users of specific substances. We will determine whether genetic variants, genes, and pathways impact VL suppression and CD4 recovery by ART regimen. Aim 2. Determine patterns and predictors of HIV treatment toxicities in the current treatment era such as liver and renal injury, cognitive decline, and frailty overall and by subgroups including current and prior IDU, and users of specific substances. We will identify genetic variants, genes, and pathways that impact outcomes. Aim 3. Identify impulsivity predictors and outcomes as measured by delayed discounting (DD) among PLWH overall, current and prior IDU, and users of specific substances. We will examine associations between impulsivity and key HIV care cascade outcomes including engagement in care, ART initiation, VL suppression, and ART adherence and other risk behaviors. We will identify genetic variants, genes, and pathways associated with impulsivity and the associations with specific drug use patterns and these outcomes. Aim 4. Apply a systems pharmacology approach to identify biological pathways between ART mode of action and liver toxicity. We will also identify biological pathways that are affected by interactions between clinically relevant ART regimens and injection drug use. We will leverage the comprehensive clinical data and specimen biorepository of the Centers for AIDS Research Network of Integrated Clinical Systems (CNICS) cohort. CNICS data include >70,000 assessments of substance use to date, detailing prior and current substance use, routes of use, and patterns and frequency of use. We will use extensive genetic data already available on 8977 PLWH and add new genotyping for 5000 additional PLWH. We will focus on response to ART, ART toxicities, and HIV care cascade steps using state of the art epidemiology and genetic analyses to address critically important gaps in scientific knowledge.